Process for the production of tocopheryllike compounds



Patented Feb. 23, 1943 2,311,887

-(iUN lTEDy STAT-ES PATENT. OFFICE PROCESS FOR THE PRODUCTION OFTOCOPHERYLLIKE CODIPOUNDS Max Tishler, Rahway, and Clarence C.Christman, Colonia, N. J assignors to Merck & 00., Inc., Rahway, N. J acorporation of New Jersey No Drawing. Application February 7, 1941,

Serial No. 377,844

3 Claims. (01. 260-338) This invention relates to tocopheryl comsulfurylchloride, sulfuryl bromide, hydrogen pounds, and to improved processesfor the chloride, hydrogen bromide, etc.,- the correspondproduction ofpure synthetic -tocopherol. 7 in h lides Of the for l a-Tocopherol, anantisterility compound may OCOQH3 be prepared by reacting phytol or aphytyl halide I with 2,3,5 trimethyl hydroquinone (2,3,5 trimethylp-dihydroxy-benzene) inthe presence of X H an acidic substance. Theknownmethods for CHZCH,(IJ CWHH isolating and purifying crudeu-tocopherolare: I

. 3 (1) Distillation of the mixture under highly re- 600cm or d qPressure I where X is -halogen, are formed. The bromide A serles o r t rp i adsorptlons occurs as miscroscopic platelets melting at about Bothof these prior art methods possess dis- 75460 P chloride occurs as finemicroswpic advantages which are objectionable from the r meltmg at3390111; practical manufacturing standpoint. The pure2,5,6-tr1methyl-3-('y-hydroxy-p yem- The first mentioned method istedious, and Y rODhytyI) -1,4-dihydroxybenzene.is then cyrequiresredistillation inorder to obtain a. pure chzed the Chromane,u'tocopherol- The product. The second method requires cumbercyclizationStep process is m t j. some equipment, and furthermore, a-to'copherol Whave, dlscovelje that lf'thls g 15 tends to become air-oxidized duringchr'omatoa out 'u t speclfic Substances the graphicrad-sorpfiomtocopherol obtained is pure and freev from dark We have now discovered amethod for u if color. Accord ng to our nvention, the preferred ingcruded-tocopherol without resort to either reagents for the cychzatlonstep are distillation 0r chromatoeraphi'ne- (1) Stannous chloride,hydrochloric acid, and

According to our invention, the crude C(- dioxanqr tocopherol isOxidized. preferably b means of (2) Zinc chloride, acetic acid, andsmall amounts either ferric chloride or gold chloride, to 2,5,6- of i dst, I

trimethyl-3-(' -hydroxy-[i -dihydrophytyl) 1,4-' benzoquinone, which is,then reduced for Known mixtures of reagents for the cyc11za ample, bysodium hydrosulfite or by catalytic hyhydmquinqnes to qhromanqsi slfch 3lmi y rop yty -d' y roxybenzene hus obtained is a solid, which isinsoluble in' pethat'the 11.56 of Such mlxtures evert wlth very troleumether, and, therefore, can be readily l4'dlhydrox5fbenzene' results m. tisolated from the oxidation reaction mixture, and '9 P Whmh cannot bepurified e by is easily purified. It issurprising that the saiddlstlllatlon' f f d lA-dihydroxybenzene occurs as a solid, because steps0 z E i' i g'f 2,5,6-trimethyl-3-(v hydroxy av dihydrophytmn g y be 1 m9 Y tyD-IA-benzoquin'one itself is' a liquid which 0 the 66 does notsolidify even at -25 C. Our new 1,4- 0 dihydroxybenzene ischaracterizedas a white,

waxy-like solid melting atabout 84-86 C., and Reaction 1130- CH;

which rapidlybecomes colored on exposure to air Egg 1 3 due tooxidation. -toco 1ic o1 11=o ca suit-earrin Our new 1,4-dihydroxybenzeneforms a crys- 1 v f talline diacetate which occurs in the form of 0 andothersubstances needles melting at 65 C. and has the formula I V on000011 I i 3 H30 CH3 H3O CH3 +[H] om 11+ OH I a-tOOIJPllBlO] I HaCCHzCHzC-C1eHas HaC- OHzCH2(|3 CuHaa V H 7 OH. H v 000cm Theoi-tocopherol thus produced'ispure and;

when it is .reductively acetylated with acetic shows the usualbiological response in rats when anhydride, zinc dust, and pyridine at 0C. When fed at a 3 mg. dose. I this diacetate is treated with ahalogenating The following examples willillustratemethods agent, such asacetyl chloride or acetyl bromide, 1 of carrying outthepresentinvention, butiit is to be understood that these examples are given byway of illustration .and not of limitation.

Example I To a solution of 10 grams of a crude reaction mixturecontaining a-tocopherol is addeda" solution of 13.5 grams of ferricchloride hexahydrate in 85% methyl alcohol. After standing for about 15minutes at room temperature, the mixture is heated to boiling forminutes and then diluted with water. The mixture is extracted withether,

and the ether layer after washing-Withwateris concentrated to a reddishoil. The oil is-sus pended in 100 cc. methanol and to the'mixture isadded a fresh solution of grams of sodium hydrosulfite in 20 cc. water.(The reduction may also be accomplished-by" bubbling hydrogen' throughthe mixture in the presence of Raneys nickel, or catalysts prepared fromplatinum or palladium.) After shaking for hour the mixture is dilutedwith three volumes: of water and then extracted with /2 volume ofpetroleum ether. The petroleum ether extract is then chilled at 0 C.whereby thew2,5,6-trimethyl-3- ('y-hydroxy-[L' -dihydrophytyl)Vr 1,4-(dihydroxybenzene separates as a whitewaxysolid- The mixture. .iscentrifuged. the-'motheiiliquor de-' canted, the solid washed welLwith..cold..petr.o1eum.. ether, and the mixturecentrifuged againj.Byirepeating this process several times, the 1,4-dihyJ- droxybenzene isobtained substantially ,pure.

The solid -1,4-dihydroxybenzene ,is then-,dis+ solved in..50 cc.dioxane, and. to this is addedS gramsof stannous chloride and 7 cc.concen-i trated hydrochloric acid.. .Themixture, is boiled underrefiuxfor sixhours. .Th'e'goolorless mix-L ture. is dilutedwithfwater.andgextracted with petroleum ether. The. petroleumethr. layeris washed with water, dried over" anhydrous magnesium sulfate, andconcentrated underreduced pressure. The residue, which is very-paleyellow, is substantially pure a-tocopherolt: ii

In place of dioxane, stannouschlor'ide and hydrochloric acid,"a mixtureof acetic acid, zinc chlorideandzinc-dust may beused. .Inthe latterwashed rwith aqueous sodium. bicarbonate, dried over magnesium sulfate;and concentrated to dryness:

The a-tOCODhBIOl isolated in this -.mannershows-the usualbiologicalresponse inrats when fed at a 3- mg.- dose.

Example II A mixture of 1 gm. of 2,5,5-t1i1118thYI-3-(7-hydroxy-flqdihydrophytyl) 1,4-dihydroxybenzene, 1 gm. of zinc dust; 10cc. of acetic anhydride,

and six drops of pyridine is stirred-Joy handgat 0 C. for one hour;After separating the*zinc;

Example III'Q' Onepgrambf crude a-tocopherol is oxidized with goldchloride, and subjected to reductive terinstance; the reaction productisdiluted with water; extracted with -petroleum .ether,. the -lat-.

'and extracted with ether.

acetylation by the method outlined above. Without crystallizingtheproduct, the oily, diacetate is dissolved in 5 cc. acetyl bromide andallowed tostand at room temperature for 14 hours. The mixture is thenadded cautiously to ice water After washing the ether extracts withwater, and with aqueous sodium bicarbonate, they are concentrated to anoil. I On the addition of 1 cc. of ether and 4 cc.

of methanol,crystallization sets in. The 2,5,6-

trimethyl-3-(vbromO -,8,'y dihydrophytyl) 1,4- dihydroxybenzenediacetate separates as microscopic platelets which melt at about -76" C.

The bromide is recrystallized by dissolving in a small amount of warmether and adding. two volumes of methanol. The melting point is notaltered by-recrystal1ization.---A solutionof mgs. of the bromide in lcc; carbon tetrachloride shows no-optical rotationin a polarimeter.

Example IV On'e gram of CIUdBa-tOCOphB-IOI is convertedinto the oilydiacetate, and then :allo'wed to stand with' acetylzchloride at roomtemperature for 14 hours.- The product is worked. up in .the same manneras the corresponding-bromide described above. The2,5,6-trimethyl-3-(ey-chloro-fifl-dh.

hydrophytyl)-1,4-dihydroxybenzene diacetate is recrystallized fromether-methanol,-and melts at 76-7'l- "C.' When warmed with'alcoholicsilver nitrate, ilver chloride precipitates.

Example V Onegram of 2,5,6-trimethyl-3- ('y-l1yd1'oxy-p,v.-

- dihydrophytyl) r1,4-dihydroXybenz-ene, diacetate.

is added to 25 cc. of a saturated solution-of hydrogen chloride inacetic ,acid. .Aftei standing. in .the

refrigerator for 14 hours. the solution is added .toice-water andworkedup. asin. the. case. oflthe.

acetyl. chloride reaction..- Tli..yield .ofchloride is almostquantitative and it melts at 37.5 76", .C. Upon .'recrystalliz'ationfrom ether-methanolit melts at 7.6-:77"C. .andshowsthe same...crysta1structure as the 2,5,6-t1imethy1-3r'('Y-ChIOI'Drfi/Y- dihydrophytyl)-'l,4-dihydroxybenzene, diacetate described. in Example. IV.-'.(Finemicroscopic needles.) A mixed melting point of theptwo chloridesshows nodepression.

Example VI Theaddition ofhydrogen bromide :to the 2,5,6- trimethyl-3-('y-hydroxy-fl,'y-dihydrophytyl-) '-1,4- dihydroxy benzene diacetate iscarried outin 40% hydrogen bromide in acetic acid; 'As a two' phasesystem is formed, themixture-is shakenfor 18 hours,;during which time asolid separates. The

product, obtained in almost quantitative yield,

melts at 6'l-68 "-C. It has the following probable formula (IL-kc.

A careful fractionationfrom ether-methanol and from ether itself,separates the mixture into a less soluble bromide (M. P. 75-76) whichshows no melting point lowering when mixed with the bromide described inExampleIIIfand a more soluble fraction melting at (iii-66v .C.

Modifications may. be made in carrying out the present invention withoutdeparting from the hydroxy benzene by treatment thereof with stannouschloride, hydrochloric acid, and dioxane, and recovering purea-tocopherol.

3. The process comprising cycliaing 2,5,6-tril methyl-S-(y-hydroxy-Qy-dihydrophytyl) -1,4-dihydroxy benzene by treatment thereofwith stannous chloride, hydrochloric acid, and dioxane at an elevatedtemperature, and concentrating a petroleum-ether extract of the mixtureto obtain 10 pure oc-tOCOPhGIOl.

MAX TISHLER. CLARENCE C. CHRISTMAN.

